Letter pubs.acs.org/NanoLett
Cite This: Nano Lett. XXXX, XXX, XXX−XXX
Near-Infrared Afterglow Luminescent Aggregation-Induced Emission Dots with Ultrahigh Tumor-to-Liver Signal Ratio for Promoted Image-Guided Cancer Surgery Xiang Ni,†,§ Xiaoyan Zhang,†,§ Xingchen Duan,† Han-Liang Zheng,‡ Xiao-Song Xue,‡ and Dan Ding*,† †
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Sciences, and ‡State Key Laboratory of Elemento-Organic Chemistry, and College of Chemistry, Nankai University, Tianjin 300071, China
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ABSTRACT: Afterglow imaging through the collection of persistent luminescence after the stopping of light excitation holds enormous promise for advanced biomedical uses. However, efficient near-infrared (NIR)-emitting afterglow luminescent materials and probes (particularly the organic and polymeric ones) are still very limited, and their in-depth biomedical applications such as precise image-guided cancer surgery are rarely reported. Here, we design and synthesize a NIR afterglow luminescent nanoparticle with aggregationinduced emission (AIE) characteristics (named AGL AIE dots). It is demonstrated that the AGL AIE dots emit rather-high NIR afterglow luminescence persisting over 10 days after the stopping of a single excitation through a series of processes occurring in the AIE dots, including singlet oxygen production by AIE luminogens (AIEgens), Schaap’s dioxetane formation, chemiexcitation by dioxetane decomposition, and energy transfer to NIRemitting AIEgens. The animal studies reveal that the AGL AIE dots have the innate property of fast afterglow signal quenching in normal tissues, including the liver, spleen, and kidney. After the intravenous injection of AGL AIE dots into peritoneal carcinomatosis bearing mice, the tumor-to-liver ratio of afterglow imaging is nearly 100-fold larger than that for fluorescence imaging. The ultrahigh tumor-to-liver signal ratio, together with low afterglow background noise, enables AGL AIE dots to give excellent performance in precise image-guided cancer surgery. KEYWORDS: Afterglow imaging, aggregation-induced emission luminogens, Schaap’s dioxetane, image-guided cancer surgery, nanoparticle
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However, afterglow-image-guided cancer surgery has been rarely reported up to the present,15 which urgently calls for highly efficient afterglow luminescent probes. To date, besides several inorganic persistent luminescent nanoparticles (e.g., rare-earth heavy metal ion based ones),16−22 only a few kinds of organic and polymeric afterglow luminescent materials have been reported.6,23−29 For instance, Pu et al. has very recently developed a semiconducting polymer nanoparticle based on poly[2methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEHPPV)6,30 that can emit effective afterglow luminescence through oxidation of vinyl bonds in PPV to yield unstable dioxetane intermediates, followed by slow degradation into PPV-aldehyde and the release of photons.6 Generally, such organic and polymeric materials show the advantages of high biological safety, good biodegradability, facile processability,
fterglow luminescence, also called persistent luminescence, refers to the sustained luminescent process after the stopping of light excitation, which holds tremendous potential to advance the biomedical field due to the innate strengths including independence to external light source, excellent signal-to-background ratio, and superior sensitivity to fluorescence.1−4 Despite a number of exciting studies involving in vivo utilizations of afterglow luminescence,5−10 its in-depth biomedical applications are still limited compared to fluorescence mainly due to the narrow range of afterglow luminescent materials and probes. For example, image-guided cancer surgery using near-infrared (NIR) fluorescence has been clinically used as a powerful strategy to help the surgeon excise tumors faster and more accurately,11 and abundant NIR fluorescent probes including the Food and Drug Administration (FDA)-approved indocyanine green have been explored for this application.12−14 The enormous merits of afterglow luminescence, particularly the far lower tissue background noise, decidedly makes it a more-desirable modality for the intraoperative guidance of tumor resection. © XXXX American Chemical Society
Received: September 30, 2018 Revised: December 5, 2018
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DOI: 10.1021/acs.nanolett.8b03936 Nano Lett. XXXX, XXX, XXX−XXX
Letter
Nano Letters Scheme 1. Synthetic Routes to (A) Compounds 3 and 4 as well as (B) TPE-DCM and TPE-Ph-DCM
and flexible surface functionalization.31−33 With a similar luminescence mechanism to MEH-PPV, Schaap’s adamantylidene-1,2-dioxetane, which is known as a chemiluminescent compound, can also be considered as one type of afterglow luminescent material that shows unique advantages such as analyte of interest-activated persistent luminescence and
bioimaging at the cellular level.34−46 Nevertheless, Schaap’s dioxetanes suffer from severe signal quenching when interacting with water.47−49 Although the surfactant-dye adduct approach is capable of improving the luminescent process,50 it is significantly hampered by the toxicity concern, and this method hardly leads to a bathochromic shift of the B
DOI: 10.1021/acs.nanolett.8b03936 Nano Lett. XXXX, XXX, XXX−XXX
Letter
Nano Letters
Scheme 2. Schematic Illustration of the Mechanism for Amplified NIR Afterglow Luminescence of the AGL AIE Dota
a White light pre-irradiation makes TPE-Ph-DCM generate 1O2, which reacts with compound 3 to afford 1,2-dioxetane-bearing compound 10. The compound 10 slowly degrades to produce excited-state compound 4 (chemiexcitation), which then transfers its energy back to the nearby TPE-PhDCM, realizing NIR afterglow luminescence of the AGL AIE dots.
emission to the near-infrared (NIR) region.37,51 In recent years, Shabat and co-workers have contributed greatly to the amplification of the emission efficiency of Schaap’s dioxetanes and concurrent red-shift of the emission wavelength under physiological conditions by either conjugating traditional fluorophore or directly introducing functional substituent at different positions of the phenol core.52−55 These exciting pioneered explorations make Schaap’s dioxetanes possible for practical biomedical uses, although the light emission quantum yields of currently existing NIR-emitting Schaap’s dioxetane derivatives (most being
